Non-ionic X-ray contrast agents constitute a very important class of pharmaceutical compounds produced in large quantities. 5-[N-(2,3-dihydroxypropyl)-acetamido]-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide (“iohexol”), 5-[N-(2-hydroxy-3-methoxypropyl)acetamido]-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide (“iopentol”) and 1,3-bis(acetamido)-N,N′-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane (“iodixanol”) are important examples of such compounds. They generally contain one or two triiodinated benzene rings.
The industrial production of non-ionic X-ray contrast agents involves a multistep chemical synthesis. To reduce the cost of the final product, it is critical to optimize the yield in each step. Even a small increase in yield can lead to significant savings in a large scale production. In particular, iodine is one of the most expensive reagent in the process. It is thus especially important to obtain a high yield with few by-products and minimal wastage for each synthetic intermediate involving an iodinated compound. Furthermore, improved purity of a reaction intermediate, especially at the latter stage of synthesis, is essential in providing a final drug substance fulfilling regulatory specification such as those expressed on US Pharmacopeia. In addition to economic and regulatory concerns, the environmental impact of an industrial process is becoming an increasingly significant consideration in the design and optimization of synthetic procedures.
One process by which iodixanol (1,3-bis(acetamido)-N,N′-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane) can be prepared is according to Scheme 1 below starting from 5-nitroisophthalic acid. See also U.S. Pat. No. 6,974,882. As part of the established acetylation process, intermediate 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide) (“Compound B”) is acetylated to give overacetylated 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (“Compound A”). Subsequently overacetylated Compound A is deacetylated to remove O-acetyl groups formed during the previous acetylation reaction to give Compound A. After deacetylation, Compound A can be purified (e.g., by crystallization). The purified Compound A can then be isolated. The isolated Compound A can then be dried for storage or it may be used directly in the production of iodixanol (e.g., dimerization of Compound A in the presence of epichlorohydrin results in the formation of iodixanol).

Consequently, the conversion of Compound B to Compound A is a key and important step in the both the small-scale and industrial scale production of iodixanol.
There exists a need for effective and efficient processes for the industrial scale production of intermediates such as 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (“Compound A”). The present invention, as described below, answers such a need by providing alternative downstream semi-continuous processes for the production of Compound A that gives a significant increase in yield and significant reduction in energy consumption and process time.